Search

Your search keyword '"Anstee, Natasha S."' showing total 31 results
Start Over Author "Anstee, Natasha S."
31 results on '"Anstee, Natasha S."'

1. Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG

Author

Loo, Sun, Roberts, Andrew W., Anstee, Natasha S., Kennedy, Glen A., He, Simon, Schwarer, Anthony P., Enjeti, Anoop K., D’Rozario, James, Marlton, Paula, Bilmon, Ian A., Taper, John, Cull, Gavin, Tiley, Campbell, Verner, Emma, Hahn, Uwe, Hiwase, Devendra K., Iland, Harry J., Murphy, Nick, Ramanathan, Sundra, Reynolds, John, Ong, Doen Ming, Tiong, Ing Soo, Wall, Meaghan, Murray, Michael, Rawling, Tristan, Leadbetter, Joanna, Rowley, Leesa, Latimer, Maya, Yuen, Sam, Ting, Stephen B., Fong, Chun Yew, Morris, Kirk, Bajel, Ashish, Seymour, John F., Levis, Mark J., and Wei, Andrew H.

Published
2023
Full Text
View/download PDF

2. Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia

Author

Moujalled, Donia M., Brown, Fiona C., Chua, Chong Chyn, Dengler, Michael A., Pomilio, Giovanna, Anstee, Natasha S., Litalien, Veronique, Thompson, Ella, Morley, Thomas, MacRaild, Sarah, Tiong, Ing S., Morris, Rhiannon, Dun, Karen, Zordan, Adrian, Shah, Jaynish, Banquet, Sebastien, Halilovic, Ensar, Morris, Erick, Herold, Marco J., Lessene, Guillaume, Adams, Jerry M., Huang, David C. S., Roberts, Andrew W., Blombery, Piers, and Wei, Andrew H.

Published
2023
Full Text
View/download PDF

3. Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias

Author

Thijssen, Rachel, Diepstraten, Sarah T., Moujalled, Donia, Chew, Edward, Flensburg, Christoffer, Shi, Melissa X., Dengler, Michael A., Litalien, Veronique, MacRaild, Sarah, Chen, Maoshan, Anstee, Natasha S., Reljić, Boris, Gabriel, Sarah S., Djajawi, Tirta M., Riffkin, Chris D., Aubrey, Brandon J., Chang, Catherine, Tai, Lin, Xu, Zhen, Morley, Thomas, Pomilio, Giovanna, Bruedigam, Claudia, Kallies, Axel, Stroud, David A., Bajel, Ashish, Kluck, Ruth M., Lane, Steven W., Schoumacher, Marie, Banquet, Sébastien, Majewski, Ian J., Strasser, Andreas, Roberts, Andrew W., Huang, David C.S., Brown, Fiona C., Kelly, Gemma L., and Wei, Andrew H.

Published
2021
Full Text
View/download PDF

6. Single-cell Rapid Capture Hybridization sequencing (scRaCH-seq) to reliably detect isoform usage and coding mutations in targeted genes at a single-cell level

Author

Peng, Hongke, primary, Jabbari, Jafar S., additional, Tian, Luyi, additional, Chua, Chong Chyn, additional, Anstee, Natasha S., additional, Amin, Noorul, additional, Wei, Andrew H., additional, Davidson, Nadia M., additional, Roberts, Andrew W., additional, Huang, David C. S., additional, Ritchie, Matthew E., additional, and Thijssen, Rachel, additional

Published
2024
Full Text
View/download PDF

9. Data from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia

Author

Sabatier, Marie, primary, Birsen, Rudy, primary, Lauture, Laura, primary, Mouche, Sarah, primary, Angelino, Paolo, primary, Dehairs, Jonas, primary, Goupille, Léa, primary, Boussaid, Ismael, primary, Heiblig, Maël, primary, Boet, Emeline, primary, Sahal, Ambrine, primary, Saland, Estelle, primary, Santos, Juliana C., primary, Armengol, Marc, primary, Fernández-Serrano, Miranda, primary, Farge, Thomas, primary, Cognet, Guillaume, primary, Simonetta, Federico, primary, Pignon, Corentin, primary, Graffeuil, Antoine, primary, Mazzotti, Céline, primary, Avet-Loiseau, Hervé, primary, Delos, Océane, primary, Bertrand-Michel, Justine, primary, Chedru, Amélie, primary, Dembitz, Vilma, primary, Gallipoli, Paolo, primary, Anstee, Natasha S., primary, Loo, Sun, primary, Wei, Andrew H., primary, Carroll, Martin, primary, Goubard, Armelle, primary, Castellano, Rémy, primary, Collette, Yves, primary, Vergez, François, primary, Mansat-De Mas, Véronique, primary, Bertoli, Sarah, primary, Tavitian, Suzanne, primary, Picard, Muriel, primary, Récher, Christian, primary, Bourges-Abella, Nathalie, primary, Granat, Fanny, primary, Kosmider, Olivier, primary, Sujobert, Pierre, primary, Colsch, Benoit, primary, Joffre, Carine, primary, Stuani, Lucille, primary, Swinnen, Johannes V., primary, Guillou, Hervé, primary, Roué, Gael, primary, Hakim, Nawad, primary, Dejean, Anne S., primary, Tsantoulis, Petros, primary, Larrue, Clément, primary, Bouscary, Didier, primary, Tamburini, Jerome, primary, and Sarry, Jean-Emmanuel, primary

Published
2023
Full Text
View/download PDF

10. Supplementary Information v.2 from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia

Author

Sabatier, Marie, primary, Birsen, Rudy, primary, Lauture, Laura, primary, Mouche, Sarah, primary, Angelino, Paolo, primary, Dehairs, Jonas, primary, Goupille, Léa, primary, Boussaid, Ismael, primary, Heiblig, Maël, primary, Boet, Emeline, primary, Sahal, Ambrine, primary, Saland, Estelle, primary, Santos, Juliana C., primary, Armengol, Marc, primary, Fernández-Serrano, Miranda, primary, Farge, Thomas, primary, Cognet, Guillaume, primary, Simonetta, Federico, primary, Pignon, Corentin, primary, Graffeuil, Antoine, primary, Mazzotti, Céline, primary, Avet-Loiseau, Hervé, primary, Delos, Océane, primary, Bertrand-Michel, Justine, primary, Chedru, Amélie, primary, Dembitz, Vilma, primary, Gallipoli, Paolo, primary, Anstee, Natasha S., primary, Loo, Sun, primary, Wei, Andrew H., primary, Carroll, Martin, primary, Goubard, Armelle, primary, Castellano, Rémy, primary, Collette, Yves, primary, Vergez, François, primary, Mansat-De Mas, Véronique, primary, Bertoli, Sarah, primary, Tavitian, Suzanne, primary, Picard, Muriel, primary, Récher, Christian, primary, Bourges-Abella, Nathalie, primary, Granat, Fanny, primary, Kosmider, Olivier, primary, Sujobert, Pierre, primary, Colsch, Benoit, primary, Joffre, Carine, primary, Stuani, Lucille, primary, Swinnen, Johannes V., primary, Guillou, Hervé, primary, Roué, Gael, primary, Hakim, Nawad, primary, Dejean, Anne S., primary, Tsantoulis, Petros, primary, Larrue, Clément, primary, Bouscary, Didier, primary, Tamburini, Jerome, primary, and Sarry, Jean-Emmanuel, primary

Published
2023
Full Text
View/download PDF

11. Supplementary Figures S1-S22 from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia

Author

Sabatier, Marie, primary, Birsen, Rudy, primary, Lauture, Laura, primary, Mouche, Sarah, primary, Angelino, Paolo, primary, Dehairs, Jonas, primary, Goupille, Léa, primary, Boussaid, Ismael, primary, Heiblig, Maël, primary, Boet, Emeline, primary, Sahal, Ambrine, primary, Saland, Estelle, primary, Santos, Juliana C., primary, Armengol, Marc, primary, Fernández-Serrano, Miranda, primary, Farge, Thomas, primary, Cognet, Guillaume, primary, Simonetta, Federico, primary, Pignon, Corentin, primary, Graffeuil, Antoine, primary, Mazzotti, Céline, primary, Avet-Loiseau, Hervé, primary, Delos, Océane, primary, Bertrand-Michel, Justine, primary, Chedru, Amélie, primary, Dembitz, Vilma, primary, Gallipoli, Paolo, primary, Anstee, Natasha S., primary, Loo, Sun, primary, Wei, Andrew H., primary, Carroll, Martin, primary, Goubard, Armelle, primary, Castellano, Rémy, primary, Collette, Yves, primary, Vergez, François, primary, Mansat-De Mas, Véronique, primary, Bertoli, Sarah, primary, Tavitian, Suzanne, primary, Picard, Muriel, primary, Récher, Christian, primary, Bourges-Abella, Nathalie, primary, Granat, Fanny, primary, Kosmider, Olivier, primary, Sujobert, Pierre, primary, Colsch, Benoit, primary, Joffre, Carine, primary, Stuani, Lucille, primary, Swinnen, Johannes V., primary, Guillou, Hervé, primary, Roué, Gael, primary, Hakim, Nawad, primary, Dejean, Anne S., primary, Tsantoulis, Petros, primary, Larrue, Clément, primary, Bouscary, Didier, primary, Tamburini, Jerome, primary, and Sarry, Jean-Emmanuel, primary

Published
2023
Full Text
View/download PDF

12. Supplementary Table S15 from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia

Author

Sabatier, Marie, primary, Birsen, Rudy, primary, Lauture, Laura, primary, Mouche, Sarah, primary, Angelino, Paolo, primary, Dehairs, Jonas, primary, Goupille, Léa, primary, Boussaid, Ismael, primary, Heiblig, Maël, primary, Boet, Emeline, primary, Sahal, Ambrine, primary, Saland, Estelle, primary, Santos, Juliana C., primary, Armengol, Marc, primary, Fernández-Serrano, Miranda, primary, Farge, Thomas, primary, Cognet, Guillaume, primary, Simonetta, Federico, primary, Pignon, Corentin, primary, Graffeuil, Antoine, primary, Mazzotti, Céline, primary, Avet-Loiseau, Hervé, primary, Delos, Océane, primary, Bertrand-Michel, Justine, primary, Chedru, Amélie, primary, Dembitz, Vilma, primary, Gallipoli, Paolo, primary, Anstee, Natasha S., primary, Loo, Sun, primary, Wei, Andrew H., primary, Carroll, Martin, primary, Goubard, Armelle, primary, Castellano, Rémy, primary, Collette, Yves, primary, Vergez, François, primary, Mansat-De Mas, Véronique, primary, Bertoli, Sarah, primary, Tavitian, Suzanne, primary, Picard, Muriel, primary, Récher, Christian, primary, Bourges-Abella, Nathalie, primary, Granat, Fanny, primary, Kosmider, Olivier, primary, Sujobert, Pierre, primary, Colsch, Benoit, primary, Joffre, Carine, primary, Stuani, Lucille, primary, Swinnen, Johannes V., primary, Guillou, Hervé, primary, Roué, Gael, primary, Hakim, Nawad, primary, Dejean, Anne S., primary, Tsantoulis, Petros, primary, Larrue, Clément, primary, Bouscary, Didier, primary, Tamburini, Jerome, primary, and Sarry, Jean-Emmanuel, primary

Published
2023
Full Text
View/download PDF

13. C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis inFLT3-Mutant Leukemia

Author

Sabatier, Marie, primary, Birsen, Rudy, additional, Lauture, Laura, additional, Mouche, Sarah, additional, Angelino, Paolo, additional, Dehairs, Jonas, additional, Goupille, Léa, additional, Boussaid, Ismael, additional, Heiblig, Maël, additional, Boet, Emeline, additional, Sahal, Ambrine, additional, Saland, Estelle, additional, Santos, Juliana C., additional, Armengol, Marc, additional, Fernández-Serrano, Miranda, additional, Farge, Thomas, additional, Cognet, Guillaume, additional, Simonetta, Federico, additional, Pignon, Corentin, additional, Graffeuil, Antoine, additional, Mazzotti, Céline, additional, Avet-Loiseau, Hervé, additional, Delos, Océane, additional, Bertrand-Michel, Justine, additional, Chedru, Amélie, additional, Dembitz, Vilma, additional, Gallipoli, Paolo, additional, Anstee, Natasha S., additional, Loo, Sun, additional, Wei, Andrew H., additional, Carroll, Martin, additional, Goubard, Armelle, additional, Castellano, Rémy, additional, Collette, Yves, additional, Vergez, François, additional, Mansat-De Mas, Véronique, additional, Bertoli, Sarah, additional, Tavitian, Suzanne, additional, Picard, Muriel, additional, Récher, Christian, additional, Bourges-Abella, Nathalie, additional, Granat, Fanny, additional, Kosmider, Olivier, additional, Sujobert, Pierre, additional, Colsch, Benoit, additional, Joffre, Carine, additional, Stuani, Lucille, additional, Swinnen, Johannes V., additional, Guillou, Hervé, additional, Roué, Gael, additional, Hakim, Nawad, additional, Dejean, Anne S., additional, Tsantoulis, Petros, additional, Larrue, Clément, additional, Bouscary, Didier, additional, Tamburini, Jerome, additional, and Sarry, Jean-Emmanuel, additional

Published
2023
Full Text
View/download PDF

14. Pretransplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines posttransplant clinical outcome

Author

Loo, Sun, primary, Dillon, Richard, additional, Ivey, Adam, additional, Anstee, Natasha S., additional, Othman, Jad, additional, Tiong, Ing Soo, additional, Potter, Nicola, additional, Jovanovic, Jelena, additional, Runglall, Manohursingh, additional, Chong, Chyn Chua, additional, Bajel, Ashish, additional, Ritchie, David, additional, Gray, Kelli, additional, Yeoh, Zhi Han, additional, McBean, Michelle, additional, Gilkes, Amanda, additional, Thomas, Ian, additional, Johnson, Sean, additional, Russell, Nigel H., additional, and Wei, Andrew H., additional

Published
2022
Full Text
View/download PDF

16. ALLG AMLM26 Phase 1B/2 Study Investigating Novel Therapies to Target Early Relapse and Clonal Evolution As Pre-Emptive Therapy in AML (INTERCEPT): A Multi-Arm, Precision-Based, Recursive, Platform Trial

Author

Wei, Andrew H, primary, Iland, Harry J, additional, Reynolds, John, additional, Loo, Sun, additional, Chua, Chong Chyn, additional, Westerman, David, additional, Tiong, Ing S, additional, Ivey, Adam, additional, Blombery, Piers, additional, Anstee, Natasha S, additional, Koldej, Rachel M, additional, Curtis, David J., additional, Kipp, David, additional, Ritchie, David, additional, Ross, David M, additional, Souza, Amanda, additional, Collins, Jenny, additional, Bajel, Ashish, additional, Grove, Carolyn, additional, Marlton, Paula, additional, Roberts, Andrew W, additional, Pemmaraju, Naveen, additional, Patel, Keyur P., additional, Loghavi, Sanam, additional, Konopleva, Marina, additional, Daver, Naval, additional, and DiNardo, Courtney D., additional

Published
2022
Full Text
View/download PDF

17. High Deliverability of a Midostaurin Triplet Regimen Incorporating Venetoclax and Low Dose Cytarabine in Non-Adverse Cytogenetic Risk Acute Myeloid Leukaemia: A Sub-Analysis of the Australasian Leukaemia Lymphoma Group (ALLG) Intervene Study

Author

Chua, Chong Chyn, primary, Anstee, Natasha S, additional, Enjeti, Anoop Kumar, additional, Hiwase, Devendra, additional, Marlton, Paula, additional, Bajel, Ashish, additional, Tan, Shuh Ying, additional, Morris, Edward S., additional, Ma, Chun-Kei-Kris, additional, Grove, Carolyn, additional, Cooney, Julian, additional, Beligaswatte, Ashanka, additional, Koldej, Rachel M, additional, Ting, Stephen B, additional, Perera, Travis, additional, Johnston, Amanda, additional, Reynolds, John, additional, Ritchie, David, additional, and Wei, Andrew H, additional

Published
2022
Full Text
View/download PDF

18. High Sensitivity Detection of FLT3-ITD Measurable Residual Disease By Deep Sequencing Prior to Hematopoietic Cell Transplant Is Highly Prognostic for Outcome in Acute Myeloid Leukemia

Author

Loo, Sun, primary, Dillon, Richard, additional, Anstee, Natasha S, additional, Tiong, Ing S, additional, Ivey, Adam, additional, Potter, Nicola, additional, Othman, Jad, additional, Runglall, Manohursingh, additional, Jovanovic, Jelena, additional, Gilkes, Amanda, additional, Thomas, Ian, additional, Johnson, Sean, additional, Russell, Nigel H., additional, and Wei, Andrew H., additional

Published
2021
Full Text
View/download PDF

19. Results of a Phase 2, Randomized, Double-Blind Study of Sorafenib Versus Placebo in Combination with Intensive Chemotherapy in Previously Untreated Patients with FLT3-ITD Acute Myeloid Leukemia (ALLG AMLM16)

Author

Wei, Andrew H, Kennedy, Glen A, Morris, Kirk L, Grigg, Andrew, He, Simon, Schwarer, Anthony, Ting, Stephen B, Enjeti, Anoop Kumar, Yuen, Sam, D'Rozario, James, Latimer, Maya, Marlton, Paula, Bilmon, Ian, Taper, John, Cull, Gavin, Tiley, Campbell, Verner, Emma, Hahn, Uwe H, Hiwase, Devendra K, Iland, Harry, Murphy, Nichloas, Ravanathan, Sundra, Nguyen, Uyen, Ong, Doen Ming, Loo, Sun, Tiong, Ing-Soo, Wall, Meaghan, Anstee, Natasha S, Levis, Mark, Murray, Michael, Rawling, Tristan, Leadbetter, Joanna, Bajel, Ashish, and Roberts, Andrew W

Published
2020
Full Text
View/download PDF

20. The Impact of Sorafenib on Phospho-FLT3 Inhibition and FLT3-ITD MRD after Chemotherapy: Correlative Studies from the Phase 2 Randomized Study of Sorafenib Versus Placebo in Combination with Intensive Chemotherapy in Previously Untreated Patients with FLT3-ITD Acute Myeloid Leukemia (ALLG AMLM16)

Author

Anstee, Natasha S, Pomilio, Giovanna, Levis, Mark, MacRaild, Sarah, Murray, Michael, Rawling, Tristan, Kennedy, Glen A, Grigg, Andrew, Schwarer, Anthony, Enjeti, Anoop Kumar, D'Rozario, James, Marlton, Paula, Bilmon, Ian, Ivey, Adam, Ong, Doen Ming, Roberts, Andrew W, and Wei, Andrew H

Published
2020
Full Text
View/download PDF

21. Acquired Mutations in BAX Confer Resistance to BH3 Mimetics in Acute Myeloid Leukemia

Author

Moujalled, Donia M, primary, Brown, Fiona C, additional, Pomilio, Giovanna, additional, Anstee, Natasha S, additional, Litalien, Veronique, additional, Thompson, Ella R, additional, Morley, Thomas, additional, MacRaild, Sarah, additional, Chua, Chong C, additional, Banquet, SéBastien, additional, Chanrion, Maia, additional, Maragno, Ana-Leticia, additional, Schoumacher, Marie, additional, Herold, Marco J, additional, Lessene, Guillaume, additional, Geneste, Olivier, additional, Huang, David C.S., additional, Roberts, Andrew W, additional, Blombery, Piers, additional, and Wei, Andrew, additional

Published
2020
Full Text
View/download PDF

22. Continuous mitotic activity of primitive hematopoietic stem cells in adult mice

Author

Morcos, Mina N.F., primary, Zerjatke, Thomas, additional, Glauche, Ingmar, additional, Munz, Clara M., additional, Ge, Yan, additional, Petzold, Andreas, additional, Reinhardt, Susanne, additional, Dahl, Andreas, additional, Anstee, Natasha S., additional, Bogeska, Ruzhica, additional, Milsom, Michael D., additional, Säwén, Petter, additional, Wan, Haixia, additional, Bryder, David, additional, Roers, Axel, additional, and Gerbaulet, Alexander, additional

Published
2020
Full Text
View/download PDF

27. Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo

Author

Carrington, Emma M, primary, Zhan, Yifan, additional, Brady, Jamie L, additional, Zhang, Jian-Guo, additional, Sutherland, Robyn M, additional, Anstee, Natasha S, additional, Schenk, Robyn L, additional, Vikstrom, Ingela B, additional, Delconte, Rebecca B, additional, Segal, David, additional, Huntington, Nicholas D, additional, Bouillet, Philippe, additional, Tarlinton, David M, additional, Huang, David CS, additional, Strasser, Andreas, additional, Cory, Suzanne, additional, Herold, Marco J, additional, and Lew, Andrew M, additional

Published
2017
Full Text
View/download PDF

29. Impact of elevated anti-apoptotic MCL-1 and BCL-2 on the development and treatment of MLL-AF9AML in mice

Author

Anstee, Natasha S., Bilardi, Rebecca A., Ng, Ashley P., Xu, Zhen, Robati, Mikara, Vandenberg, Cassandra J., and Cory, Suzanne

Abstract

Many acute myeloid leukaemias (AMLs) express high levels of BCL-2 and MCL-1, especially after therapy. To test the impact of these anti-apoptotic proteins on AML development and treatment, we used haemopoietic reconstitution to generate MLL-AF9AMLs expressing BCL-2or Mcl-1transgenes. AMLs with elevated BCL-2 or MCL-1 had a higher proportion of mature myeloid cells but, like conventional MLL-AF9AMLs, were readily transplantable. Short-term cell lines established from multiple primary AMLs of each genotype were tested in vitro for susceptibility to chemotherapeutics currently used for treating AML (daunorubicin, etoposide, cytarabine); the proteasome inhibitor bortezomib; CDK7/9 inhibitors; and BH3 mimetics, which bind and inhibit pro-survival proteins. The BH3 mimetics tested, alone and in combination with the other drugs, were: ABT-737 which, like its clinical counterpart navitoclax, targets BCL-2, BCL-XLand BCL-W; BCL-2-specific ABT-199 (venetoclax); BCL-XL-specific A-1331852; and S63845, a new MCL-1-specific BH3 mimetic. As single agents, daunorubicin and bortezomib had the greatest efficacy. Elevated MCL-1 or BCL-2 reduced sensitivity to daunorubicin but, surprisingly, not to bortezomib. MCL-1 markedly enhanced resistance to ABT-737 and ABT-199 but not S63845, and BCL-2 increased resistance to S63845 but not to ABT-737 or ABT-199. Notable synergies were achieved by combining BH3 mimetics with daunorubicin: S63845 increased the sensitivity of both MCL-1 and BCL-2 overexpressing MLL-AF9AMLs, and ABT-737 aided in killing those overexpressing BCL-2. Synergy between daunorubicin and ABT-199 was also apparent in vivo, although not curative. Impressive synergistic responses were achieved for human MLL-fusion AML cell lines treated with daunorubicin plus either ABT-737, ABT-199 or S63845, and with ABT-199 plus S63845, with or without daunorubicin. Our data suggest that AML patients may benefit from combining conventional cytotoxic drugs with BH3 mimetics targeting BCL-2 or MCL-1 or, if tolerated, both these agents.

Published
2019
Full Text
View/download PDF

30. Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Author

Anstee, Natasha S, Vandenberg, Cassandra J, Campbell, Kirsteen J, Hughes, Peter D, O’Reilly, Lorraine A, and Cory, Suzanne

Abstract

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by pro-survival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the pro-apoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lprmice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+CD4–CD8–B220+) characteristic of Faslpr/lprmice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types.

Published
2017
Full Text
View/download PDF

31. C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress-Induced Ferroptosis in FLT3-Mutant Leukemia.

Author

Sabatier M, Birsen R, Lauture L, Mouche S, Angelino P, Dehairs J, Goupille L, Boussaid I, Heiblig M, Boet E, Sahal A, Saland E, Santos JC, Armengol M, Fernández-Serrano M, Farge T, Cognet G, Simonetta F, Pignon C, Graffeuil A, Mazzotti C, Avet-Loiseau H, Delos O, Bertrand-Michel J, Chedru A, Dembitz V, Gallipoli P, Anstee NS, Loo S, Wei AH, Carroll M, Goubard A, Castellano R, Collette Y, Vergez F, Mansat-De Mas V, Bertoli S, Tavitian S, Picard M, Récher C, Bourges-Abella N, Granat F, Kosmider O, Sujobert P, Colsch B, Joffre C, Stuani L, Swinnen JV, Guillou H, Roué G, Hakim N, Dejean AS, Tsantoulis P, Larrue C, Bouscary D, Tamburini J, and Sarry JE

Subjects
Humans, CCAAT-Enhancer-Binding Protein-alpha genetics, CCAAT-Enhancer-Binding Protein-alpha metabolism, fms-Like Tyrosine Kinase 3 genetics, fms-Like Tyrosine Kinase 3 metabolism, Fatty Acids, Mutation, Oxidative Stress, Protein Kinase Inhibitors therapeutic use, Cell Line, Tumor, Ferroptosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism
Abstract

Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)-stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application., Significance: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501., (©2023 American Association for Cancer Research.)

Published
2023
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results